Antihistamine formulations for soft capsule dosage forms

ABSTRACT

The invention herein relates to a pharmaceutical composition containing loratadine and derivatives thereof which is suitable for use in soft capsule dosage forms. A pharmaceutical composition according to the invention comprises loratadine and derivatives thereof in a pharmaceutically effective amount; and a solvent system comprising a mixture of medium chain fatty acids. The loratadine compositions exhibit good solubility and storage stability while maintaining bioavailability of the drug. The compositions also permit high concentrations of solubilized loratadine per total fill volume and thereby permit the use of smaller capsules to deliver the same dosage of drug.

RELATED APPLICATION DATA

This application is a continuation-in-part (CIP) of U.S. patentapplication Ser. No. 09/909,313 filed Jul. 20, 2001, now U.S. Pat. No.6,720,002 issued Apr. 13, 2004.

FIELD OF THE INVENTION

The invention relates to the field of pharmaceutical compositions. Inparticular, the invention pertains to pharmaceutical formulationscontaining antihistamines, such as, loratadine and its derivatives thatare formulated for use in conjunction with soft capsules.

BACKGROUND OF THE INVENTION

Two identified histamine receptors are the receptors H-1 and H-2. TheH-1 receptors mediate the response antagonized by conventionalantihistamines. H-1 receptors are present in the mammalian skin, ileumand bronchial smooth muscle.

Non-narcotic or non-sedating hydrophobic antihistamine compounds such asloratadine and its derivatives are known. Loratadine was first describedin U.S. Pat. No. 4,282,233 to Vilani. Loratadine is an H-1 histaminereceptor protein antagonist which binds to peripheral H-1 receptors asdiscussed in Quercia et al., Hosp. Formul., 28, p. 137–53 (1993).Loratadine is useful as an antihistamine and has little or no sedativeeffects. Thus, loratadine provides an antihistamine effect while stillallowing the user to perform mental or physical functions requiring highlevels of concentration. A variety of other therapeutic treatments usingloratadine alone or in combination with other active ingredients havebeen suggested, such as treatment of seasonal or perennial rhinitis,allergic asthma, and motion sickness. See Aberg et al., U.S. Pat. No.5,731,319, for example. Antiarrhythmic uses, such as treatment of atrialfibrillation (AF), have also been suggested, as described in Buckland etal., U.S. Pat. No. 6,110,927.

Loratadine derivatives which share antihistamine properties ofloratadine have also been developed. Active metabolites such asdecarbalkoxylated forms of loratadine have been of interest. One suchmetabolite derivative is8-chloro-6,11-dihydro-11-(4-piperidylidine)-5H-benzo-[5,6]-cyclohepta-[1,2-b]pyridine, also known as descarboethoxyloratadine (DCL) which isdescribed in U.S. Pat. No. 4,659,716. U.S. Pat. No. 5,595,997 to Aberget al discloses methods of utilizing DCL for the treatment of allergicrhinitis and other disorders without adverse side effects.

Other patents relating to loratadine or a chemically relatedantihistamine, including any pharmaceutically acceptable salt thereof,in various dosage forms include U.S. Pat. No. 5,100,675 to Cho et al.;U.S. Pat. No. 4,990,535 to Cho et al.; and U.S. Pat. No. 5,314,697 toKwan et al.

Oral dosage forms, such as loratadine-containing tablets and syrups, areknown and marketed under the names Claritin®, Claratin Reditabs® andClaratin-D® 24-Hour etc. (commercially available from Schering-PloughCorporation, NJ).

These commercial products are described in U.S. Pat. No. 4,282,233 toVillani; U.S. Pat. No. 4,659,716 to Villani; U.S. Pat. No. 4,863,931 toSchumacher et al.; U.S. Pat. No. 6,132,758 to Munayyer et al. U.S. Pat.No. 6,132,758 discloses an antihistaminic syrup stabilized againstdegradation of the active ingredient by the addition of about 0.05 to 5mg/mL of an amino-polycarboxylic acid. This patent teaches that undercertain storage conditions losses of active agent can occur.

U.S. Pat. No. 4,910,205 to Kogan et al discloses a transdermallyacceptable composition comprising an effective amount of loratadine orits decarbalkoxylation product, about 40–70% weight % of a volatilesolvent, about 5–50% by weight of a fatty acid ester and about 2–60% ofan essential oil.

While syrup, solid and fast dissolving dosage forms are available forloratadine type antihistamines, there presently exists a need for a softcapsule dosage form. The soft capsule dosage form has many advantagesknown to those skilled in the art, however, formulating hydrophobicdrugs into solutions for encapsulation into a soft capsule can presentmany problems. Oral delivery systems for hydrophobic drugs are known.Lacy et al. U.S. Pat. No. 6,096,338 describes delivery systems forhydrophobic drugs including histamine H-1 receptor antagonists such asloratadine. The carrier systems disclosed include a digestible oil,preferably mixtures of partial or complete esters of medium chain fattyacids, and a pharmaceutically acceptable surfactant component comprisinga hydrophilic surfactant containing a transesterification product ofpolyoxyethylene glycol with glycerol esters of capric and/or caprylicacids. This surfactant disperses the oil in vivo without substantiallyinhibiting in vivo lipolysis of the oil. The reference does not,however, specifically address the problems associated with storagestability and recrystallization of loratadine and its derivatives insoft capsule dosage forms.

Hydrophobic solvents are preferred for use in soft capsules so as toreduce the hydrophilic nature of the fill, wherein migration of waterthrough the soft capsular material into the fill composition can causerecrystallization and precipitation of the active ingredient understorage conditions. One problem associated with hydrophobic solvents,however, is that they are known to adversely affect bioavailability ofthe drug. Compounds such as loratadine are susceptible torecrystallization and therefore experience the solvent system challengesassociated with soft capsules. Ideally, a solvent system for loratadineand its derivatives is one which is hydrophobic, protonic andwater-dispersible.

There thus exists a need for improved pharmaceutical formulationscontaining loratadine and derivatives thereof for use in soft capsuleswhich solubilize loratadine and exhibit long-term storage stability atambient conditions without recrystallization. There is also a need for asolvent system which does not adversely affect bioavailability of theactive ingredient. Even more desirable would be a formulation whichsatisfies both of these criteria and also increase the fillconcentration of loratadine. This would permit the use of smaller sizecapsules for a given dose of active.

SUMMARY OF THE INVENTION

The invention provides for a pharmaceutical composition comprisingloratadine and its derivatives together with a solvent system for use insoft capsules. Loratadine compositions of the invention exhibitunexpected and improved solubilization properties at ambient storageconditions over extended period of time without recrystallization andprecipitation of loratadine. The inventive composition also permitshigher concentrations of loratadine to be delivered within a given fillvolume. As a result, the total amount of fill volume needed toadminister the same dosage of loratadine is reduced, and smaller capsulesizes can be used thereby improving patient comfort and reducingmanufacturing costs.

The invention provides a pharmaceutical composition for use in softcapsules comprising loratadine and derivatives thereof and a solventsystem comprising a mixture of mono- and diglycerides of medium chainfatty acids. In a more preferred embodiment the invention provides apharmaceutical composition that additionally comprises a dispersant. Ina most preferred embodiment the dispersant comprises povidone andpolyoxyethylene sorbitan fatty acid ester (e.g., Polysorbate™ 80).

There is further disclosed a pharmaceutical composition for use in softcapsule dosage form consisting essentially of:

a) loratadine and derivatives thereof present in an amount of about 6.3%by weight of the total composition;

b) mono- and di-glycerides of medium chain fatty acids present in anamount of about 87% by weight of the total composition;

c) povidone present in an amount of about 6.3% by weight of the totalcomposition; and

d) polyoxyethylene sorbitan fatty acid ester present in an amount ofabout 0.8% by weight of the total composition.

There is also disclosed a pharmaceutical composition for use in softcapsule dosage forms consisting essentially of:

a) decarbalkoxylated loratadine derivative in a pharmaceuticallyeffective amount;

b) mono- and di-glycerides of medium chain fatty acids comprisingcaprylic acid and capric acid;

c) povidone; and

d) polyoxyethylene sorbitan fatty acid ester.

There is further disclosed a soft capsule dosage form comprising a fillcomposition consisting essentially of:

a) loratadine and derivatives thereof in a pharmaceutically effectiveamount;

b) a mixture of mono- and diglycerides of medium chain fatty acids;

c) povidone;

d) polyoxyethylene sorbitan fatty acid ester; and

-   -   wherein said soft capsule has a capsule size of 5 minim or less.

Loratadine is the drug name given to the compound known as ethyl4-(8-chloro-5,6-dihydro-11H-benzo┌5,6┐cyclohepta┌1,2-b┐pyridin-11-ylidene)-1-piperidinecarboxylate.A structure for this compound is:

Loratadine derivatives include compounds having the structural formulaof loratadine and having substituents differing from that of loratadineand having substantially the same chemical and therapeutic properties.Loratadine derivatives include, but are not limited to,decarboalkokylated forms of loratadine, such as8-chloro-6,11-dihydro-1-(4-piperidylidine)-5H-benzo-[5,6]-cyclohepta-[1,2-b]pyridine, also known as descarboethoxyloratadine (DCL); and azatadine.As used herein and in the claims the phrase “loratadine and derivativesthereof” means loratadine or any chemically related antihistamine,including any pharmaceutically acceptable salt thereof. Chemicallyreacted antihistamines include any halogenatedH-benzo-cyclohepta-pyridine.

Loratadine and derivatives thereof can be present in an amount of about6.3% or less by weight of the total fill composition. Typically,loratadine and derivatives thereof can be present in an amount of about6.3% to about 3.0% by weight of the total fill composition.

Solvent systems which can be used in accordance with the invention arethose which are both moderately lipophilic and have hydrogen bondingcapability. Preferably, the solvent system has a hydrophilic lipophilicbalance (HLB) value ranging from about 3 to about 7, more preferablyranging from about 4 to about 5. The preferred solvent system of theinvention contains a mixture of mono- and diglycerides of medium chainfatty acids. Preferred mixtures of mono- and diglycerides of mediumchain fatty acids comprise mixtures of caprylic and capric acid. Mostpreferred as the mixture of mono- and diglyceride medium chain fattyacids is CAPMUL™ MCM-C8 (available from Abitec Corporation, Northampton,England). The mono- and diglyceride mixture can be present in an amountof about 89.0% by weight or less of the total fill composition. WhenCAPMUL™ MCM-C8 is used, it is preferably present in an amount rangingfrom about 89.0% to about 70.0%, more preferably about 89.0% to about80%, by weight of the total fill composition.

The solvent system can further comprise a dispersant composition toenhance uniform dispersibility of the fill in water or gastric juices.The amount of the additional dispersant, however, is present in amountsufficient to enhance uniform dispersion of the fill in water or gastricjuices without significantly increasing the volume of the fill. When adispersant is used, it is preferred that the dispersant be present in anamount of 8.0% by weight of the fill or less. More preferred is adispersant present in an amount of from about 7.5% to about 5.0%, mostpreferably from about 7.5% to about 7.0%, by weight of the total fillcomposition.

A preferred dispersant is a mixture of povidone (polyvinylpyrrolidone)and polyoxyethylene sorbitan fatty acid ester. Suitable polyoxyethylenesorbitan fatty acid esters which can be used include, but are notlimited to, Polysorbate™ 80. Mixtures of povidone and Polysorbate™ 80can preferably be present in a weight ratio of about 10:1 to about 15:1,respectively. Other polyoxyethylene sorbitan fatty acid esters which canbe used include Polysorbate™ 40, Polysorbate™ 60, Polysorbate™ 20 andPolysorbate™ 120.

Compositions according to the invention do not require the presence ofadditional ingredients such as additives and stabilizers typicallyassociated with soft capsule fill formulations. Without these additionalingredients higher concentrations of loratadine and derivatives thereofcan be obtained within smaller fill volumes as compared to existingformulations.

The invention further provides a soft dosage form having apharmaceutical composition comprising loratadine and derivatives thereofand a solvent system having a mixture of medium chain mono- anddiglycerides. In one embodiment, the invention includes a soft capsulecomprising a storage stable composition having 10 mg of loratadine insolubilized state in a capsule size as small as 3 minims.

DETAILED DESCRIPTION OF THE INVENTION

The loratadine compounds of the invention can be prepared according tothe method described in Villani U.S. Pat. No. 4,282,233, the entire textof which is incorporated herein by reference. The starting materials andreagents to prepare loratadine and its derivatives are well known in theart and readily available, and loratadine and its derivatives can besynthesized using conventional organic synthesis techniques. Metabolicderivatives of loratadine, such as decarbalkoxylated forms ofloratadine, can be prepared by removal of the carbethoxy moietyaccording to methods known in the art and as described in U.S. Pat. No.4,659,716, the entire text of which is incorporated herein by reference.For example, loratadine can be refluxed in the presence of sodiumhydroxide and ethanol to remove the carbethoxy moiety from thepiperidine ring of the compound structure.

Solvent systems which can be used in accordance with the invention arethose which are both moderately lipophilic and have hydrogen bondingcapability. Preferably, the solvent system has a hydrophilic lipophilicbalance (HLB) value ranging from about 3 to about 7, more preferablyranging from about 4 to about 5. Suitable solvent systems include, butare not limited to, polyglycolized glycerides (such as LABRAFIL® WL2609BS available from Gattefosse, Binfield, U.K.), propylene glycolmonolaurate (such as LAUROGLYCOL™ 90 available from Gattefosse),propylene glycol monocaprylate (such as CAPRYOL™ 90 available fromGattefosse), and mono- and diglyceride medium chain fatty acids. Mostpreferred is the mono-, diglyceride medium chain fatty acid mixtureCAPMUL™ MCM C8 (commercially available from Abitec Corporation).

The solvent system can further comprise a dispersant composition toenhance uniform dispersibility of the fill in water. The amount of theadditional dispersant, however, is present in amount sufficient toenhance uniform dispersion of the fill in water or gastric juiceswithout significantly increasing the volume of the fill. When adispersant is used, it is preferred that the dispersant be present in anamount of 8.0% by weight of the fill or less. Most preferred is adispersant present in an amount of from about 7.5% to about 7.0% byweight of the total fill composition.

The dispersant composition used in accordance with the invention can bea combination of povidone together with a surfactant. Suitablesurfactants which can be used include, but are not limited to, non-ionicsurfactants having an HLB value ranging from about 14 to about 17;polyoxyethylene sorbitan fatty acid esters, such as Polysorbate™ 40,Polysorbate™ 80, Polysorbate™ 60, Polysorbate™ 20, and Polysorbate™ 120;ethoxylated aliphatic alcohols, such as Oleth-20 (Volpo™ 20 availablefrom Croda, Inc., Parsippany, N.J.), Ceteareth-20 (Volpo™ CS-20available from Croda, Parsippany, N.J.); and caprylocaproyl macrogol-8glycerides (LAUROGLYCOL™ 90 available from Gattefosse).

A preferred dispersant is a mixture of povidone and Polysorbate™ 80.Mixtures of povidone (polyvinyl pyrrolidone) and Polysorbate™ 80(polyoxyethylene sorbitan fatty acid monooleate) can be present in aratio of about 10:1 to about 15:1.0, respectively.

Soft capsules containing pharmaceutical compositions can be preparedusing conventional and known encapsulation techniques, such as thatdescribed in Stroud et al., U.S. Pat. No. 5,735,105, the entire text ofwhich is incorporated herein by reference. In general, the formulationis deposited between two opposing ribbons of a gel composition. Thecomposition of the ribbons may include gelatin, modified starches, gums,carrageenans and mixtures thereof.

Carrageenans are water-soluble gums comprising linear polysaccharideswith a sugar backbone of alternating units consisting of galactose unitslinked by 1,3-β-D-linkages, as well as 1,4-α-D-linkages. The fundamentalproperties of iota, kappa and lambda are a function of the number andposition of the ester sulfate groups. Preferred carrageenan capsulematerials are those comprising iota-carrageenan. Iota-carrageenancontains approximately 30% by weight 3,6 anhydro-D-galactose and 32%ester sulfate by weight. Particularly preferred are iota-carrageenanmaterials described in Tanner et al., U.S. Pat. No. 6,340,473, theentire text of which is incorporated herein by reference, whichcomprises iota-carrageenan, modified starch, plasticizer and a dibasicbuffer system. Carrageenan-containing capsule materials are availableunder the tradename VEGICAPS™ and available from Cardinal Health, Inc.,Somerset, N.J.).

Modified starches that can be used in accordance with the inventioninclude hydroxypropylated starches, acid thinned starches and the like.The only native starch determined to be functional with iota-carrageenanin preparing the capsular material films of the invention is potatostarch, and the term “modified starch” is meant to include native,unmodified potato starch. In general, modified starches are productsprepared by chemical treatment of starches, for example, acid treatmentstarches, enzyme treatment starches, oxidized starches, cross-bondingstarches, and other starch derivatives. It is preferred that themodified starches be derivatized wherein side chains are modified withhydrophilic or hydrophobic groups to thereby form more complicatedstructure with a strong interaction between side chains.

Suitable plasticizers include the materials used for the same purpose inthe manufacture of mammalian gelatin capsules. Representativeplasticizers are any of a variety of polyhydric alcohols such asglycerin, sorbitol, propylene glycol, polyethylene glycol and the like.Other plasticizers can include saccharides and polysaccharides, whichcan be prepared by hydrolysis and/or hydrogenation of simple or complexpolysaccharides.

Other components can also be incorporated into the carrageenan capsulecompositions provided they do not alter the melting point/fusion pointcharacteristics of the film. Representative of these additionalcomponents, typically added during the molten state of the capsulecomposition, include flavoring agents, opacifying agents, preservatives,embrittlement inhibiting agents, colorants, dyes and pigments, anddisintegrants. Use of conventional pharmaceutical or food gradeingredients are acceptable.

Those skilled in the art will appreciate what capsule materialcompositions are suitable. The opposing ribbons are then run between twodie rollers having die pockets thereon the surface of which correspondsto the configuration of the desired soft capsule. The composition issealed within the fused casing.

When formulated in accordance with the invention, a 10 mg loratadinedose can be accommodated by a 5 minim or less size oval soft capsule. A10 mg loratadine dose can be contained within a capsule size as small asa 3 minim size oval soft capsule. Capsule size volumes of the inventionare herein expressed in terms of minims. A minim is a pharmaceuticalvolumetric unit of measure wherein 1 minim=0.0616 cc.

Soft capsule forms, such as soft gelatin or Vegicaps™ soft capsules,containing the loratadine compositions of the invention can be orallyadministered to patients in need of H1 receptor antagonist orantihistamine treatment.

The invention can be further illustrated by the following Examples:

EXAMPLE 1

Process of Preparing Loratadine Formulation

CAPMUL™ MCM C8, povidone, and Polysorbate™ 80 were combined. The mixturewas heated to about 60° C. until the povidone was completely dissolved.Loratadine was added to the mixture and the resulting mixture wasstirred until the loratadine was completely dissolved. The mixture wascooled to room temperature. The formulations prepared are summarized inTable 1 below:

TABLE 1 Loratadine Formulations with Mono-diglyceride of Medium ChainFatty Acid Solvent System Formula 4-1 Formula 4-2 Formula 4-3(mg/capsule) (mg/capsule) (mg/capsule) Ingredient (% w/w) (% w/w) (%w/w) Cap-  139 mg 201.5 mg  264 mg mul ™ MCM- C8  (86.9%)  (88.2%) (89.2%) Povidone   10 mg   15 mg   20 mg  (6.3%)  (6.6%)  (6.8%)Polysorbate ™ 80   1 mg  1.5 mg   2 mg  (0.8%)  (0.7%)  (0.7%)Loratadine   10 mg   10 mg   10 mg  (6.3%)  (4.4%)  (3.4%) Fill weight 160 mg   228 mg  296 mg (100.0%) (100.0%) (100.0%) Fill 2.60 minim 3.70 minim 4.80 minim volume (minim) Density = 1.0 g/ml

EXAMPLE 2

Preparation of Comparative Loratadine Formulations

In a manner similar to that of Example 1, the following formulationswere prepared in accordance with the corresponding ingredients andproportions:

TABLE 2 Loratadine Formulations with PEG (Macrogol ™ 400)/PropyleneGlycol Solvent System Formula 1-1 Formula 1-2 Formula 1-3 Formula 1-4(mg/capsule) (mg/capsule) (mg/capsule) (mg/capsule) Ingredient (% w/w)(% w/w) (% w/w) (% w/w) PEG 400 260 mg 305 mg 360 mg 408 mg (Macrogol ™(87.8%) (88.4%) (88.7%) (88.9%) 400) Propylene 26 mg 30 mg 36 mg 41 mgGlycol (8.8%) (8.7%) (8.9%) (8.9%) Loratadine 10 mg 10 mg 10 mg 10 mg(3.4%) (2.9%) (2.5%) (2.2%) Fill 296 mg 345 mg 406 mg 459 mg weight(100.0%) (100.0%) (100.0%) (100.0%) Capsule 5 minim oval 6 minim oval7.5 minim oval 8.5 minim oval size (minim) Density = 1.08 g/ml

TABLE 3 Loratadine Formulations with PEG (Macrogol ™ 400)/PropyleneGlycol/Povidone Solvent System Formula 2-1 Formula 2-2 Formular 2-3Formula 2-4 (mg/capsule) (mg/capsule) (mg/capsule) (mg/capsule)Ingredient (% w/w) (% w/w) (% w/w) (% w/w) PEG 400 260 mg 285 mg 336 mg381 mg (Macrogol ™ (81.8%) (82.6%) (82.8%) (83.0%) 400 Propylene 26 mg28 mg 34 mg 38 mg Glycol (8.2%) (8.1%) (8.4%) (8.3%) Povidone 22 mg 22mg 26 mg 30 mg (6.9%) (6.4%) (6.4%) (6.5%) Loratadine 10 mg 10 mg 10 mg10 mg (3.1%) (2.9%) (2.5%) (2.2%) Fill 318 mg 345 mg 406 mg 459 mgweight (100.0%) (100.0%) (100.0%) (100.0%) Capsule 5 minim oval 6 minimoval 7.5 minim oval 8.5 minim oval size (minim) Density = 1.1 g/ml

TABLE 4 Loratadine Formulations with PEG (Macrogol ™ 400)/PropyleneGlycol/Polyoxyethylene 20 sorbitan monooleate (Polysorbate 80) SolventSystem Formula 3A-1 Formula 3A-2 Formula 3B-1 Formula 3B-2 (mg/capsule)(mg/capsule) (mg/capsule) (mg/capsule) Ingredient (% w/w) (% w/w) (%w/w) (% w/w) PEG 400 89 mg 108 mg 96 mg 116 mg (Macrogol ™ (36.2%)(36.5%) (39.0%) (39.2%) 400) Propylene 13 mg 16 mg 13 mg 15 mg Glycol(5.3%) (5.4%) (5.3%) (5.1%) Polysorbate ™ 134 mg 162 mg 127 mg 155 mg 80(54.5%) (54.7%) (51.6%) (52.4%) Loratadine 10 mg 10 mg 10 mg 10 mg(4.1%) (3.4%) (4.1%) (3.4%) Fill 246 mg 296 mg 246 mg 296 mg weight(100.0%) (100.0%) (100.0%) (100.0%) Capsule 4 minim oval 5 minim oval 4minim oval 5 minim oval size (minim)

EXAMPLE 3

Comparative Storage Stability Study of Loratadine Compositions

The storage stability test was conducted on each of the aboveformulations by subjecting samples of each formulation to varyingconditions. Each sample was prepared by either filling 3DXHB gel poucheswith the formulation or a screw-capped brown glass bottle. Some of thesamples were tested using pouches that were unsealed, and some of thesamples tested were sealed using fresh gel. Each pouch sample wassubjected to the following conditions: 1) 22° C. under ambient humidity,2) 30° C. under 75% relative humidity (corresponding to acceleratedsolution stability test conditions), and 3) 5° C. under ambienthumidity.

TABLE 5 Storage Stability at 5° C./Ambient Humidity of LoratadineFormulation with PEG 400/Propylene Glycol Solvent System Formulation:Container: Storage Period: Result: 1-1 Capped vial 8 months Clear/nocrystals 1-1 Open gel pouch 8 months Crystallization

As can be seen from the data in the above Table, no observablecrystallization occurred in the conventional Macrogol™ 400 formulationin the capped vials at 5° C. and ambient humidity conditions. On theother hand, the Macrogol™ 400 formulation crystallized when stored inthe open gel pouch. The results demonstrate that exposure of loratadineformulations to ambient moisture causes crystallization over time.

TABLE 6 Storage Stability at 22° C./Ambient Humidity of Loratadine FillFormulations Formulation: Container: Storage Period: Result: ALL Cappedvial 80 days Clear/no crystals 1-1 Capped vial  8 months Clear/nocrystals

As can be seen in the above Table, none of the formulations tested hadobservable crystallization during a storage period of 80 days whencontained in the capped vial at 22° C. and ambient humidity conditions.

TABLE 7 Storage Stability at 30° C./75% Relative Humidity of LoratadineFormulation with PEG 400/Propylene Glycol Solvent System Formula: 1-11-2 1-3 1-4 Days until 8 days 13 days 13 days 16 days crystallization(sealed gel pouch) Days until 5 days 10 days Not tested Not testedcrystallization (open gel pouch)

As can be seen from the above data, storage at 30° C. and 75% relativehumidity resulted in observable crystallization of the conventionalloratadine formulations in the Macrogol™ 400 solvent system, andcrystallization occurred in both sealed and open gel pouch containment.In the case of Formulas 1-1 and 1-2, crystallization occurred morerapidly in the open gel pouch than the sealed gel pouch.

TABLE 8 Storage Stability at 30° C./75% Relative Humidity of LoratadineFormulation with PEG 400/Propylene Glycol/Povidone Solvent SystemFormula: 2-1 2-2 2-3 2-4 Days until 8 days 10 days 13 days 15 dayscrystallization (sealed gel pouch) Days until 5 days 10 days Not testedNot tested crystallization (open gel pouch)

As the data shows, storage conditions of 30° C. and 75% relativehumidity of loratadine formulations with a solvent system of Macrogol™400 in combination with povidone did not prevent crystallization fromoccurring in either sealed or open gel pouches.

TABLE 9 Storage Stability at 30° C./75% Relative Humidity of LoratadineFormulation with PEG 400/Propylene Glycol/Polysorbate 80 Solvent SystemFormula: 3A-1 3A-2 3B-1 3B-2 Days until 16 days 29 days 19 days 29 dayscrystallization (sealed gel pouch)

The above data shows that loratadine formulations in a Macrogol™ 400solvent system and Polysorbate™ 80 did not prevent crystallization under30° C. and 75% relative humidity storage conditions.

TABLE 10 Storage Stability at 30° C./75% Relative Humidity of LoratadineFormulations with Mono-, Diglyceride of Medium Chain Fatty Acid SolventSystems Formula: 4-1 4-2 4-3 Days until No crystals after No crystalsafter No crystals after crystallization 1 year and 4 71 days 71 days(sealed gel months pouch) Days until Not tested No crystals after Nocrystals after crystallization 73 days 92 days (open gel pouch)

As can be seen from the above data, loratadine formulations prepared inaccordance with Formula 4-1 of the invention as described aboveexhibited no observable crystallization even after 71 days in storage at30° C. with 75% relative humidity conditions in either the open orsealed gel pouch containment. Further yet, no observable crystals werepresent in Formulation 4-1 of the invention even after 16 months in thesealed gel pouch containment.

EXAMPLE 4

Preparation of Dosage Form Comprising Loratadine and Carrageenan CapsuleMaterial

In a process similar to that set forth in Example 1, the following fillformulation containing loratadine as an active ingredient was prepared:

TABLE 11 Loratadine Fill Formulation Formula 5 (mg/capsule) Ingredient(% w/w) Capmul ™ MCM- 262.1 mg C8  (89.5%) Povidone   19 mg  (6.5%)Polysorbate ™ 80  1.9 mg  (0.6%) Loratadine   10 mg  (3.4%) Fill weight293.0 mg (100.0%) Density = 1.0 g/ml

A capsule material was prepared having the following composition:

TABLE 12 Carrageenan Capsule Material Ingredient Amount (% w/w) PurifiedWater 8.0% Disodium phosphate 1.3% anhydrous Hydroxypropyl starch 43.2%Carrageenan 14.0% Glycerin 33.5% Total: 100.00%

Carragenan (iota-form) was Satiagel USC2 obtained from Degussa TexturantSystems, Balogne, Billancou, France; and the hydroxypropyl starch wasPure-Cote B790 obtained from Grain Processing Corp., IA.Iota-carragenan, hydroxypropyl starch and anhydrous disodium phosphatewere dispersed in the liquids and molted. The obtained molten mass wascast into ribbon in the conventional manner known to those skilled inthe art. The fill formulation of Table 11 was encapsulated in thematerial of Table 12. The shell mass was pumped into an encapsulationapparatus where the capsules are formed by the rotary die process undercontrolled temperature and humidity conditions.

The resulting soft capsule dosage form was a 5 minim oval capsulecontaining 10 mg of loratadine as the active ingredient.

INDUSTRIAL APPLICABILITY

The loratadine compositions of the invention provide for the use ofloratadine in soft capsule dosage forms such as soft gelatin capsules byimproving its solubility under storage conditions without adverselyaffecting its bioavailability. The compositions of the invention offerthe additional benefit of increasing the concentration of solubilizedloratadine per total fill volume, which permits smaller fill volumes tobe used to deliver the same dosage of the drug. Accordingly, smallercapsule sizes can be used to administer the drug to patients, therebyincreasing patient comfort and reducing manufacturing costs.

The complete disclosures of all patents, patent applications andpublications are incorporated herein by reference as if each wereindividually incorporated by reference. The invention has been describedwith reference to various specific and preferred embodiments andtechniques. However, it should be understood that many variations andmodifications can be made while remaining within the spirit and scope ofthe invention.

1. A soft capsule dosage form comprising a fill composition consisting essentially of: a) a decarbalkoxylated loratadine derivative in a pharmaceutically effective amount; b) a mixture of mono- and diglycerides of medium chain fatty acids; c) povidone; d) polyoxyethylene sorbitan fatty acid ester; and wherein said soft capsule has a capsule size of 5 minim or less to about 1 minim; and wherein the soft capsule comprises a capsule material comprising carrageenan.
 2. The soft capsule dosage form according to claim 1 wherein the decarbalkoxylated loratadine derivative is descarboethoxyloratadine.
 3. The soft capsule dosage form according to claim 1, wherein said carrageenan is iota-carrageenan.
 4. The soft capsule dosage form according to claim 3, wherein the capsule material further comprises hydroxypropyl starch.
 5. The soft capsule dosage form according to claim 4, wherein the capsule material further comprises glycerin.
 6. The fast capsule dosage form according to claim 1, wherein the capsule material comprises the following formulation: a) iota-carrageenan; b) hydroxypropyl starch; c) glycerin; d) anhydrous disodium phosphate; and e) water.
 7. The soft capsule dosage form according to claim 6, wherein the capsule material further comprises an additive selected from the group consisting of flavoring agents, opacifying agents, preservatives, embrittlement inhibiting agents, colorants, dyes and pigments, and disintegrants. 